PB1776: EXPRESSION OF BCL2, BAX AND MDR1 GENES AS PHARMACOTRANSCRIPTOMIC MARKERS OF PROGNOSIS IN DE NOVO PATIENTS OF ADULT ACUTE MYELOID LEUKEMIA WITH NORMAL KARYOTYPE
Authors: Vladimir Gašić, Zlatko Pravdic, Nada Suvajdzic, Irena Marjanovic, Teodora Karan-Đurašević, Sonja Pavlović, Nataša Tošić
Journal: HemaSphere (2023)

Topic: 3. Acute myeloid leukemia - Biology & Translational Research Background: Acute myeloid leukemia (AML) is a malignancy of hematopoetic tissue which occurs due to a halt in differentiation, loss of proliferation control and dysregulated apoptosis of myeloid progenitor cells. It is the most common acute leukemia in adults, accounting for 80% of all cases. Stratification of AML patients is based on their karyotype. However, the constant introduction of new molecular markers of prognosis of AML patients calls for a different approach. In many cancers, as well as AML, dysregulation of apoptosis constitutes the basis of pathogenesis and this phenomenon is important to consider when the success of chemotherapy is in question. Another important factor of chemotherapy success is the degree of drug efflux. These factors constitute tumor resistance. Pharmacotranscriptomic markers of tumor resistance could be important targets for specific therapy, which, when applied, could improve prognosis in AML. The anti-apoptotic gene BCL2 (B-cell lymphoma protein 2) and the pro-apoptotic BAX (BCL2-associated X) expression levels are markers of non-pump tumor resistance (genes associated with apoptosis), while a marker of tumor pump resistance (gene which codes a protein associated with drug efflux) is the expression level of MDR1 (multi-drug resistance gene 1). These tumor resistance markers could have a significant impact on AML prognosis. Aims: By analyzing the gene expression profiles of BCL2, BAX and MDR1 and using statistics to identify association with clinical indicators of prognosis in adult AML patients with normal karyotype (AML-NK), the significance of these genes as molecular targets can be further elucidated. Methods: Bone-marrow samples at diagnosis were collected from 51 adult patients with AML-NK, who were treated with the same 3 + 7 protocol, followed by three consolidation cycles. Expressions of BCL2, BAX and MDR1 were analyzed using the real-time polymerase chain reaction method. Clinical data and expression values were statistically evaluated for possible associations Results: The presence of chemoresistance was found to be associated with overexpression of BCL2 (BCL2+) (p=0.018), while underexpression of BAX in patients has shown a greater affinity towards relapse (p=0.034). Evaluating the expressions of BCL2 and BAX in a combined effect has shown that 87% of patients with BAX/BCL2low status were resistant to therapy (p=0.024). BCL2+ status was associated with high expression of MDR1 (p<0.001). Likewise, high expression of MDR1 was associated with the absence of NPM1 and FLT3-ITD mutations (p=0.048 and p=0.010, respectively). Summary/Conclusion: This is the first study that focused only on AML-NK patients, when it comes to analysis of BCL2, BAX and MDR1 gene expression profiles. The results of this preliminary study have shown that high BCL2 expression would likely lead to tumor resistance from chemotherapy, making anti-BCL2 treatment a viable option in patients with this expression profile. A study on a larger group of patients could clarify the prognostic importance of the studied pharmacotranscriptomics markers, contributing to a creation of personalized treatment of adult AML-NK patients. Keywords: MDR1, Acute myeloid leukemia, Bax, BCL2